chr10-92613376-G-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Moderate
The NM_004523.4(KIF11):c.790-1G>T variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 31)
Consequence
KIF11
NM_004523.4 splice_acceptor
NM_004523.4 splice_acceptor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.84
Genes affected
KIF11 (HGNC:6388): (kinesin family member 11) This gene encodes a motor protein that belongs to the kinesin-like protein family. Members of this protein family are known to be involved in various kinds of spindle dynamics. The function of this gene product includes chromosome positioning, centrosome separation and establishing a bipolar spindle during cell mitosis. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.07631662 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.2, offset of 13, new splice context is: attaaatgttgatcttgcAGgaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 10-92613376-G-T is Pathogenic according to our data. Variant chr10-92613376-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 192301.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-92613376-G-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KIF11 | NM_004523.4 | c.790-1G>T | splice_acceptor_variant | ENST00000260731.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KIF11 | ENST00000260731.5 | c.790-1G>T | splice_acceptor_variant | 1 | NM_004523.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 28
GnomAD4 exome
Cov.:
28
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2014 | - - |
Microcephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID) Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 30, 2019 | The KIF11 c.790-1G>T variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.790-1G>T variant has been reported in one study, in which it is found in a heterozygous state in one individual with microcephaly and familial exudative vitreoretinopathy (Robitaille et al. 2014). The c.790-1G>T variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Similar variants, c.790-1G>A and c.790-2A>C, were identified in a presumed de novo heterozygous state in two individuals with microcephaly (Mirzaa et al. 2015; Li et al. 2016). Based on the collective evidence and application of the ACMG criteria, the c.790-1G>T variant is classified as pathogenic for microcephaly with or without chorioretinopathy, lymphedema or intellectual disability. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 14
DS_AL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at